Dr. Urano’s June Wolfram Research Update

Dear Friends,

It’s a spectacular Saturday morning in Saint Louis as I write this to you. I always appreciate your continued support, encouragement, and kind words.

I have received many questions regarding our ongoing clinical trial, as well as questions related to our next step lately.

Although we don’t have a concrete plan yet, we consider the following possibilities.

  1. A longer duration, More participants, Multi-center
  2. Compare the efficacy of dantrolene sodium, valproic acid, and dantrolene sodium plus valproic acid

We are also developing breakthrough treatments for Wolfram syndrome as dantrolene and valporic acid are old drugs originally developed for other medical conditions.

Here are our new plans.

  1. We have been developing a new drug designed for Wolfram syndrome  (ER stress stabilizers) together with NIH/NCATS to delay/halt the progression of the disease. Pre-clinical studies in mouse models of Wolfram have been designed. We are seeking funds to complete these studies.
  2. Regenerative therapies using a novel neurotrophic factor in combination with gene transfer technology for visual impairment have been designed. We are seeking funds for testing these new therapies in mouse models of Wolfram syndrome.

I think we are making progress, and need to speed up as we are racing against time. Thank you again for your support.

Take care,

Fumi Urano, MD

Dr. Barrett meets with Wolfram Associations across the globe

Dear Friends and colleagues,

I have been fortunate to visit the French Wolfram Association meeting in April in Paris; and the Spanish Wolfram association meeting in May in Almeria.

I was humbled by the friendship and community spirit of these families; and they were very tolerant of my poor French and Spanish language skills.

On the research front, we have just published the online mutation database of genetic variants in the Wolfram gene. This was work undertaken by Dr Dewi Astuti, and is a freely available database to support scientists worldwide. The database is available at: https://lovd.euro-wabb.org

Regarding the Phase II clinical trial, we are negotiating manufacture of the investigational medicinal product and placebo. We hope to complete this in the next 4 weeks and are still aiming to begin recruitment in the UK in November.

Thank you for all your interest and support, and I will try to provide regular updates on our progress

Sincerely,

Prof Tim Barrett

Clinical Trial Update by Fumihiko Urano, M.D.

Dear Friends,

I would like to update you about the status of our clinical trial of dantrolene sodium in patients with Wolfram syndrome. Dantrolene is a US Food and Drug Administration (FDA)-approved drug currently used for different medical conditions. Based on our data, we received orphan drug designation of dantrolene sodium for the treatment of Wolfram syndrome from US FDA and European Medicines Agency (EMA) in 2016. We also ​received the​ green light from ​the ​FDA and Washington University Medical Center to proceed to a pilot clinical trial (phase 1b) to assess the safety and efficacy of dantrolene on patient’s vision, brain functions, and diabetes.

Thanks to the generous support from the Snow Foundation in collaboration with Ellie White Foundation and other private donors, I was able to commence the clinical trial and slowly started recruiting patients. I would like to recruit at least 24 patients and hope to secure more funds to accommodate all the patients who are eligible for this trial. Stephanie Gebel​ has told me that she will do her best to make this happen. ​I was just informed ​​this week that we will receive grant funding from the National Institutes of Health (NIH) to support this trial.

​have not forgotten​ about our patients in other countries. Dr. Tim Barrett in the UK and I are closely working ​to conduct international clinical trials for Wolfram syndrome. In parallel, we keep on developing novel drugs and regenerative therapies for Wolfram syndrome. Dantrolene could be a band-aid for Wolfram, but cannot provide a cure. Thus, we need pipelines for developing breakthrough treatments.

Thank you for your continued support.

Sincerely,

Fumi Urano, MD

End Of The Year Update

Dear Friends,

My highest priority right now is to work out the logistics for the upcoming clinical trial. As our medical center announced in November this year, we plan to start a phase 1b safety clinical trial of dantrolene sodium in patients with Wolfram syndrome. Dantrolene sodium is an FDA-approved drug utilized for the treatment of muscle stiffness. We found that dantrolene could prevent the destruction of insulin-secreting beta cells in animal models of Wolfram syndrome and in brain cells differentiated from skin samples taken from patients with the illness in 2014 after the 12 years of research. This drug can target the molecular pathways altered in Wolfram syndrome in cell and animal models of Wolfram syndrome. Nobody has ever tested dantrolene in patients with Wolfram syndrome, so our first and most important objective is to make sure it’s safe. We will also closely monitor patients’ vision and brain function, as well as the function of their remaining insulin-secreting beta cells based on the data collected through our research clinic study.

The major question that I get from every patient I see is, “Is there any treatment?” As you are aware, there is currently no treatment that can slow, halt, or reverse the clinical manifestations of Wolfram syndrome including vision impairment and diabetes. I sincerely hope that this study can help change that. I have been working diligently to commence the trial early next year, hopefully in January 2017, and secure additional funding from the National Institutes of Health to recruit more patients. Please contact my nurse coordinator, Ms. Ashley Simpson (+1-314-286-1550, ashley.simpson@wustl.edu) or check our medical center’s website (http://wolframsyndrome.dom.wustl.edu/clinical-trials/) for more information. I appreciate the support from the Snow Foundation and Ellie White Foundation for the upcoming trial.

I have been working with Dr. Tim Barrett in the UK to conduct international clinical trials for Wolfram syndrome. In parallel, we keep on developing novel drugs and regenerative therapies for Wolfram syndrome.

As we near the end of this year, I would like to take this opportunity to thank you all for your continued support. You have provided patients with hope and emotional support. Together with you, we can make a difference in the future of our patients. Thank you again for your generous support and continued encouragement. You gave me the power and courage to continue. I cannot thank you enough. I hope you have a wonderful holiday season.

Sincerely,

Fumi Urano, MD

Researchers launch first clinical trial for Wolfram syndrome

The drug dantrolene is a muscle relaxant approved to treat patients with cerebral palsy, multiple sclerosis and muscle spasticity. Recent research also suggests it can prevent the destruction of insulin-secreting beta cells in animal models of Wolfram syndrome. Researchers at Washington University School of Medicine in St. Louis are beginning a clinical trial to assess the drug as a treatment for patients with Wolfram syndrome.

The drug dantrolene is a muscle relaxant approved to treat patients with cerebral palsy, multiple sclerosis and muscle spasticity. Recent research also suggests it can prevent the destruction of insulin-secreting beta cells in animal models of Wolfram syndrome. Researchers at Washington University School of Medicine in St. Louis are beginning a clinical trial to assess the drug as a treatment for patients with Wolfram syndrome.

 

Researchers at Washington University School of Medicine in St. Louis are launching a new clinical trial to assess the safety of a drug treatment for patients with the rare disease Wolfram syndrome.

Wolfram syndrome affects about one in every 500,000 people worldwide. Many of those patients die prematurely from the disease. Patients with Wolfram syndrome typically develop diabetes at a very young age and require insulin injections several times each day. The disorder also causes hearing loss, vision problems and difficulty with balance.

Although doctors treat patients’ symptoms, there have not been any therapies that slow the syndrome’s progress.

However, researchers at Washington University School of Medicine soon will test a drug treatment in 24 patients who have the genetic disorder.

The scientists previously reported in the Proceedings of the National Academy of Sciences that the drug, dantrolene — a muscle relaxant approved to treat patients with cerebral palsy, multiple sclerosis and muscle spasticity — prevents the destruction of insulin-secreting beta cells in animal models of Wolfram syndrome and in brain cells differentiated from skin samples taken from patients with the illness.

“Nobody has ever tested dantrolene in patients with Wolfram syndrome, so our first and most important objective is to make sure it’s safe,” said principal investigator Fumihiko Urano, MD, PhD, the Samuel E. Schechter Professor of Medicine. “I am very hopeful, however. The major question that I get from every patient I see is, ‘Is there any treatment?’ And until now, I’ve had to say no. With any luck, perhaps this study can help change that.”

In the mouse studies, and in experiments with brain cells made from a patient’s own stem cells, Urano previously found that dantrolene prevented death of brain cells and insulin-secreting beta cells.

Urano’s team plans to study 12 adult and 12 pediatric patients over nine months. All of the participants will undergo extensive testing before they begin taking the medication and after having taken the drug for six months. The researchers will closely monitor patients’ vision and brain function, as well as the function of their remaining insulin-secreting beta cells.

To be eligible for the study, all patients must be able to travel to the Washington University Medical Campus for testing and medication.

The study is funded by the Snow Foundation and the Ellie White Foundation. Both are advocacy groups that support Wolfram syndrome research. Urano also has applied for federal funding to support the clinical trial and wants to expand it to other medical centers.

He doubts that dantrolene can reverse the illness. “But hopefully, we can at least delay the progression of the disease,” he said.

For more information, call study coordinator Ashley Simpson at 314-286-1550, or e-mail ashley.simpson@wustl.edu.

 

Article by Jim Dryden

7th Annual Washington University Wolfram Syndrome Research Clinic Meeting

2015 Wolfram Research Clinic Update

Three Drug Targets. What is the difference?

We have identified three drug targets for Wolfram syndrome in the past two years. These are MANF, Calpain 2, and IRE1. What is the difference between these three molecules. Here is a short summary.

MANF: Enhances survival and proliferation of remaining cells.
Caplain 2: Activates cells death signal in Wolfram and Diabetes. So we need an inhibitor.
IRE1: Prevents the activation of cell death signals.
IRE1 and Calpain 2 are enzymes. So we need drugs that can control their activation levels.

MAFN is a secreted molecule. We can potentially use an artificial MANF (i.e., recombinant MANF) for treatment. Another pathway is to identify a receptor for MANF and develop a drug that can activate the MANF receptor.

Thank you for reading my blog. I always appreciate your encouragement. I think about our patients every day.

Take care,

Fumi Urano

Business man under the question mark

Business man under the question mark

The “Mini-Clinic”: News from the Wolfram Research Clinic at Washington University

imgresLast summer, we had a successful research clinic, with 24 patients and their families attending from all over the world and the US. We welcomed three new patients to our group this year and in a whirlwind 4 days, we performed 22 MRI scans and over 350 individual appointments!

Since then, we have identified additional patients that are good candidates for this study or who are interested in a clinical consultation (or both). Rather than waiting until next summer to collect the research data, we have started to bring these families in to WU one at a time. We call this a ‘mini-clinic’. Each patient undergoes the same tests with our usual wolfram research clinic doctors and investigators, staying overnight in St. Louis. So far, we have done this with 2 families, and 2 more are being scheduled. The mini-clinic has been working quite well and is a nice option for families that can’t or don’t want to travel to St. Louis in July. It also helps us get more data at a quicker pace, which is in the best interests of everyone.

We have also seen four new patients for clinical consultations and for diagnosis of Wolfram.   We are always happy to consult with patients or their physicians about whether they might have Wolfram and how to obtain testing. We can also arrange for them to have care by any of our team who has experience with Wolfram.

Thank you to all of the families for participating in all of our research, and to all of our colleagues and staff who help make the big research clinic and our new mini-clinics happen so smoothly.

Tamara Hershey, Ph.D.
Professor
Psychiatry, Neurology and Radiology
Washington University School of Medicine
Scientific Director of Clinic and PI, NIH R01 “Tracking Neurodegeneration in Early Wolfram Syndrome”

Bess Marshall, M.D.
Professor
Pediatrics
Washington University School of Medicine
Medical Director of Clinic